Hepatocellular carcinoma (HCC) is the major primary malignant tumor of the liver. Although viral etiological factors have been identified, the molecular mechanisms that contribute to tumor progression during hepatocarcinogenesis remain largely unknown. The Frizzled family of proteins is composed of ten or more seven-transmembrane proteins that act as receptors for Wnt proteins. The Wnt/Frizzled signaling network influences diverse biological processes ranging from cell fate determination to cell motility and proliferation.
β-catenin is a multifactorial protein with a role in cell-cell adhesion that involves strengthening the linkage of cadherin and α-catenin to the actin cytoskeleton. In the absence of Wnt/Frizzled signaling, β-catenin is phosphorylated by interactions with glycogen synthase kinase (GSK)-3β, and forms a complex with axin and the adenomatous polyposis coli protein (APC). Subsequently, β-catenin is targeted for degradation by the ubiquitinproteasome system. In contrast, binding of a Wnt ligand to its Frizzled receptor stabilizes intracellular β-catenin through the inhibition of GSK-3β enzymatic activity. Subsequently, β-catenin translocates into the nucleus in association with high mobility group domain factors such as Tcf/Lef. This complex is associated with transcriptional up-regulation of growth regulatory and cell migration related genes.